Mucolytic mercaptoacylamidobenzamides and process of using same

ABSTRACT

A mucolytic process is disclosed which comprises contacting N-(2-hydroxyethyl)mercaptoacetamidobenzamides or mercaptoacylamidobenzoic acids, mercaptoacetylsulfanilic acids and alkanoylthio derivatives thereof with mucus. Illustrative of compounds useful in the mucolytic process of the present invention are 4-(2-mercaptoacetamido)-benzoic acid and N-(2-mercaptoacetyl)sulfanilic acid.

CROSS REFERENCE TO RELATED APPLICATION

This application is a division of co-pending U.S. application Ser. No.579,650 filed May 21, 1975, now U.S. Pat. No. 4,005,222.

BACKGROUND OF THE INVENTION

This invention deals with mucolytic agents and a process of thebio-affecting body treatment type. More particularly, the inventionrelates to a process for liquefying mucus adaptable for use in thetreatment of mammals or for laboratory use.

A. L. Sheffner, Ann. N. Y. Acad. Sci., 106, 298-310 (1963), disclosesthat a variety of sulfhydryl containing compounds have mucolyticactivity and, in an attempt to correlate mucolytic activity and chemicalstructure, stated that compounds having a free sulfhydryl group weregenerally effective in reducing mucus viscosity. None of the compoundsdisclosed by Sheffner were of the mercaptoacylamidobenzoic or sulfonicacid type. The subject matter of A. L. Sheffner U.S. Pat. No. 3,091,569relates to N-acylated sulfhydryl compounds such as N-acetyl-L-cysteinewhich is commercially available under the trademark Mucomyst® as atopically effective mucolytic agent. U. Weiss, U.S. Pat. No. 2,520,293concerns mercaptoacetanilide derivatives and discloses antioxidantutility therefor. U.S. Pat. No. 3,809,697 issued to Martin and Comer,the inventors of the instant invention, disclose a group of1,4-bis-acylpiperazines having mucolytic properties.

It has now been found surprisingly that mercaptoacylamidobenzoic acidsdisclosed in Weiss, U.S. Pat. No. 2,520,293 andN-(2-mercaptoacetyl)sulfonic acids are topically effective mucolyticagents substantially more potent than N-acetyl-L-cysteine.

SUMMARY OF THE INVENTION

This invention relates to a process for liquefying mucus which comprisescontacting the mucus with an effective mucolytic amount of a compoundcharacterized by Formula I. ##STR1##

In Formula I, A is meta or para oriented with respect to the ##STR2##radical and is selected from the group consisting of carboxylic,sulfonic and N-(2-hydroxyethyl)carboxamide radicals represented by thesymbols CO₂ H, SO₃ H, CONHCH₂ CH₂ CH, respectively. The symbol "Alk"comprehends a divalent alkylene radical joining "S" and "CO" andcontains from one to three carbon atoms inclusive such as methylene(--CH₂ --), ethylene (--CH₂ CH₂ --), propylene (--CH₂ CH₂ CH₂ --),##STR3## R represents hydrogen whenever the "A" substitutent iscarboxylic, sulfonic, or N-(2-hydroxyethyl)carboxamide. In addition,whenever A is carboxylic or sulfonic, R can also be alkanoyl having upto eighteen carbon atoms inclusive. The salts of those substanceswherein "A" is carboxylic or sulfonic are also part of the presentinvention. The preferred salts are those prepared from pharmaceuticallyacceptable alkali metals such as sodium, potassium, calcium and basessuch as ammonia. "Pharmaceutically acceptable" as used herein todescribe the alkali metal and ammonium salts refers to those cationicspecies which do not contribute appreciably to the toxicity of theproduct nor to its pharmacological activity.

A particularly preferred group of compounds useful as mucolytic agentscomprises those of Formula I wherein Alk is methylene, R is hydrogen oracetyl, and A is carboxylic or sulfonic.

A still further preferred group of compounds comprises those substancesof Formula I wherein R is limited to hydrogen, Alk is methylene, and Ais carboxylic, sulfonic or N-(2-hydroxyethyl)carboxamide.

Particularly preferred specific compounds included within the scope ofthis invention are

N-(2-mercaptoacetyl)sulfanilic acid,

4-(2-mercaptoacetamido)benzoic acid,

3-(2-mercaptoacetamido)benzoic acid,

N-(2-hydroxyethyl)-4-(2-mercaptoacetamido)benzamide and

4-[2-(acetylthio)acetamido]benzoic acid.

Some of the aforementioned compounds are known to the art and arereported to be of value for non-medical related utilities. Both4-(2-mercaptoacetamido)benzoic acid and 3-(2-mercaptoacetamido)benzoicacid are described in U.S. Pat. No. 2,520,293 as antioxidants while thesodium salt of N-(2-mercaptoacetyl)sulfanilic acid has been described byN. S. Poonia, et al., Indian J. Appl. Chem., 27 (1) 32-33 (1964) as areagent for the colorimetric determination of potassium.

Those compounds of Formula I wherein A is carboxyl or sulfonic may bepartially or completely neutralized by adjusting the pH of a solution tobe used in the mucolytic process of the present invention. The pHadjustment is carried out by addition of suitable alkaline reactingsubstances such as sodium hydroxide, ammonium hydroxide, potassiumhydroxide, calcium hydroxide and the like. Salts of this type areconsidered biologically equivalent to the parent acid with respect tomucolytic activity. When a molar equivalent of an alkaline base isemployed, the alkaline salt form thus obtained can be recoveredaccording to conventional techniques such as evaporation, lyophylizationor precipitation with a suitable solvent. For instance, addition of 1Nsodium hydroxide to a suspension of 4-(mercaptoacetamido)benzoic acid inisopropanol-water under an atmosphere of nitrogen affords sodium4-(mercaptoacetamido)benzoate by addition of isopropanol and cooling.Ammonium 4-(mercaptoacetamido)benzoate and calcium4-(mercaptoacetamido)benzoate further illustrate pharmaceuticallyacceptable salts of the compounds of Formula I.

Compounds of Formula I are synthesized by conventional methods adaptablefor preparation of mercaptans and thio esters. For instance, U.S. Pat.No. 2,520,293 discloses preparation of 4-(2-mercaptoacetamido)benzoicacid by basic hydrolysis of N-α-(carbamylmercaptoacetyl)-p-aminobenzoicacid. This method is applicable to preparation of compounds of FormulaI, wherein R is hydrogen and A is carboxylic.

A preferred process for preparing compounds of the present inventioncharacterized by Formula I comprises reacting a compound of Formula II##STR4## wherein Alk is as defined above, X is halogen such as bromine,iodine or chlorine, B is meta or para CO₂ H, CO₂ R₂ wherein R₂ is loweralkyl of 1 to 4 carbon atoms inclusive, SO₃ H or CONHCH₂ CH₂ OH with analkali metal salt (e.g., sodium or potassium) of a thiol of the formulaR₁ --SH wherein R₁ is alkanoyl of 1 to 18 carbon atoms inclusive toprovide alkanoyl compounds of Formula III ##STR5## wherein R₁, Alk and Bare as above defined and thereafter, if desired, hydrolyzing saidalkanoyl compounds to provide the compounds of Formula I wherein R ishydrogen.

Hydrolysis of the compounds of Formula III may be carried out accordingto conventional techniques by interaction with an alkoxide such assodium or potassium methoxide or a base such as sodium or potassiumhydroxide in a reaction inert solvent such as methanol, ethanol, water,dimethylformamide, and the like. The resultant products have acidcharacter and are isolated by first neutralizing the reaction mixturewith an acid, such as acetic or hydrochloric and, then removing thesolvent.

In carrying out the reaction of the alkali metal salts of R₁ --SH withthe halogen intermediates of Formula II having a free carboxylic orsulfonic acid group, the acid function is neutralized by addition of analkali metal hydroxide such as potassium or sodium hydroxide beforereacting with the thiol.

It will be recognized by those skilled in the art that the mucolyticprocess of the present invention may be practiced in vivo as well as invitro. The in vivo process is employed where it is desirable ornecessary to liquefy mucus produced as a result of pathologicalconditions involving mucus producing tissue, particularly for examplecongestion of the respiratory system, vaginal tract and the like. The invitro process is employed where it is desirable to reduce viscosity ofmucus in order to facilitate analytical determinations or otherexamination. For instance, the compounds of Formula I can be used assputum digestants in the isolation of mycobacteria. The concentration inwhich the compounds of Formula I have been found to effectively induceliquefaction of mucus is between about 0.003 to 0.5 molar. In carryingout the in vitro mucolytic process of the present invention, an aqueoussolution or suspension of a compound of Formula I is prepared at thedesired concentration and then mixed with mucus at a ratio of about 0.2ml. of the solution or suspension of the mucolytic agent to each 1.0 ml.of mucus. Generally, satisfactory liquefaction of the mucus will beobtained within the period of about 1 to 15 minutes. It is to beunderstood that in addition to pharmaceutically acceptable salts of thecompounds characterized by Formula I, other suitable cationic speciescan be employed in the in vitro process which would be generallyprecluded in the in vivo process because of excessive toxicity.

In accordance with the in vivo process of the present invention, thecompounds of Formula I are administered in an amount sufficient toinduce liquefaction of mucus in the respiratory tract of mammals in needthereof. Intratracheal administration of the compounds of Formula I iseffected by various inhalation or instillation means such as by nosedrops, sprays, aerosols, and the like. Another suitable means ofadministration is by insufflation of micronized particles or ultra-finepowder utilizing only the energy of the inspiratory action or by use ofaerosol propellants. Solutions or suspensions having about 0.5 to 5% byweight of the mucolytic agent of Formula I are suitable for applicationby spraying with an atomizer, nebulizer, aerosol and the like.

It will be readily apparent to those skilled in the medical arts, thatthe correct dosage of a compound of Formula I to be employed with anyparticular mammalian subject is determined by the severity of thecondition requiring mucolytic therapy, as well as the age, sex, weight,and general physical condition of the subject. Individual doses rangingfrom 5-100 mg. for inhalation by man are suitable and may be repeated asrequired for the desired mucolytic effect.

The substances of Formula I are relatively non-toxic substancessubstantially free of other pharmacologic action.4-(2-Mercaptoacetamido)benzoic acid, a representative compound ofFormula I, has an approximate oral LD₅₀ of 2000 mg./kg. body weight andan approximate TD₅₀ of 250 mg./kg. body weight in the mouse. When givenintraperitoneally this compound has an LD₅₀ of 1108 mg./kg. body weight.

The following examples are only intended to illustrate the presentinvention and are not to be construed as limiting the invention in anyrespect.

EXAMPLES OF SPECIFIC EMBODIMENTS EXAMPLE 1 Mucolytic Activity ofRepresentative Compounds of Formula I

Mucolytic activity was determined using the method of J. Lieberman, Am.J. Resp. Dis., 97, 662 (1968). This is a viscometric method whichemploys a cone-plate viscometer (Brookfield Engineering Laboratories,Inc., Stoughton, Mass.). According to this method, a 2 ml. aliquot of abatch of purulent human sputum (obtained from bronchitic patients) istransferred to the center of the viscometer plate and the temperature isallowed to equilibrate. The plate is then rotated at graduallyincreasing speeds up to 100 r.p.m. during a two-minute period. Thisreduces the amount of sputum on the test plate to 1 ml. and reduces theviscosity of the specimen to a reproducible value which is necessarybecause of the thixotropic properties of sputum. The rotation is thenreduced to give a convenient reading on the instrument and a solution ofthe test drug having a volume of 0.2 ml. is then added to the sputum cupand readings as percent reduction in viscosity of the original arerecorded at time intervals of one to three minutes for a period of 15min. The test is repeated with N-acetyl-L-cysteine employing anotheraliquot of sputum to establish a control for comparison purposes.Relative molar potencies compared to N-acetyl-L-cysteine (NAC) can bedetermined by varying concentration of the test agent untilapproximately equivalent mucolytic activity is obtained. Results of thistest for representative compounds of Formula I are given below.

                  TABLE I                                                         ______________________________________                                        MUCOLYTIC ACTION - PERCENT REDUCTION IN                                       VISCOSITY Compound 1. - 4-(2-MERCAPTOACETAMIDO)                               BENZOIC ACID                                                                          NAC      Compound 1                                                   Time (min.)                                                                             0.06 Molar 0.01 Molar 0.005 Molar                                   ______________________________________                                        1         36         45         32                                            3         45         63         50                                            6         52         69         57                                            9         50         76         55                                            12        52         82         55                                            15        60         84         55                                            ______________________________________                                    

On a molar basis, Compound 1 is approximately 12 times as active asN-acetyl-L-cysteine.

                  TABLE II                                                        ______________________________________                                        MUCOLYTIC ACTION - PERCENT REDUCTION IN                                       VISCOSITY Compound 2. -3-(2-MERCAPTOACETAMIDO)                                BENZOIC ACID                                                                              NAC           Compound 2                                          Time (min.) 0.03 Molar    0.03 Molar                                          ______________________________________                                        1           33            44                                                  3           34            67                                                  6           36            81                                                  9           34            89                                                  12          34            91                                                  15          34            93                                                  ______________________________________                                    

On a molar basis, Compound 2 is substantially more active thanN-acetyl-L-cysteine.

                  TABLE III                                                       ______________________________________                                        MUCOLYTIC ACTION - PERCENT REDUCTION IN                                       VISCOSITY Compound 3. -N-(2-MERCAPTOACETYL)                                   SULFANILIC ACID                                                                       NAC      Compound 3                                                   Time (min.)                                                                             0.06 Molar 0.01 Molar 0.005 Molar                                   ______________________________________                                        1         36         46         34                                            3         45         64         47                                            6         52         66         50                                            9         50         68         50                                            12        52         77         47                                            15        60         82         44                                            ______________________________________                                    

On a molar basis, Compound 3 is approximately 10 to 12 times as activeas N-acetyl-L-cysteine.

                  TABLE IV                                                        ______________________________________                                        MUCOLYTIC ACTION - PERCENT REDUCTION IN                                       VISCOSITY Compound 4. -N-(2-HYDROXYETHYL)-4-                                  (2-MERCAPTOACETAMIDO)BENZAMIDE                                                Time  NAC       Compound 4                                                    (min.)                                                                              0.03 Molar                                                                              0.005 Molar                                                                              0.002 Molar                                                                            0.001 Molar                               ______________________________________                                        1     25        30         26       25                                        3     32        58         37       32                                        6     40        67         42       36                                        9     42        75         44       36                                        12    42        82         44       36                                        15    40        82         42       34                                        ______________________________________                                    

On a molar basis, Compound 4 is approximately 15 times as active asN-acetyl-L-cysteine.

                  TABLE V                                                         ______________________________________                                        MUCOLYTIC ACTION - PERCENT REDUCTION IN                                       VISCOSITY Compound 5. -4-[ 2-(ACETYLTHIO)ACETAMIDO]                           BENZOIC ACID                                                                              NAC           Compound 5                                          Time (min.) 0.03 Molar    0.03 Molar                                          ______________________________________                                        1           29            34                                                  3           33            42                                                  6           40            54                                                  9           40            54                                                  12          43            52                                                  15          40            48                                                  ______________________________________                                    

On a molar basis, Compound 5 is significantly more active thanN-acetyl-L-cysteine.

EXAMPLE 2

In order that the compounds of Formula I should be readily available tothose persons desiring to practice the mucolytic process of the presentinvention, the following synthetic procedures are given. The compoundnumber corresponds to the number of those substances of Formula I listedhereinabove in Tables I-V.

Compound 1

To a mixture of methyl 4-[2-(acetylthio)acetamido]benzoate (15 g., 0.056mole) in 100 ml. of ethanol is added 72 ml. (0.18 mole) of 10% sodiumhydroxide. The reaction mixture is stirred for a period of 16 hr. atroom temperature and then acidified with 32 ml. of 6 N hydrochloric acidto provide an off white solid which is collected, washed with water anddried yielding 11.2 g., (95% yield) of the mercaptobenzoic acid product.Crystallization of the solid from ethanol employing decolorizingcharcoal affords analytically pure 4-(2-MERCAPTOACETAMIDO)BENZOIC ACID,m.p. 232.0°-233.0° C. (dec.)(corr.).

Analysis. Calcd. for C₉ H₉ NO₃ S: C, 51.17; H, 4.29; N, 6.63. Found: C,51.26; H, 4.34; N, 6.49.

By substituting an equimolar amount of

methyl 4-[2-(acetylthio)propionamido]benzoate or

methyl 4-[3-(acetylthio)propionamido]benzoate

for methyl 4-[2-(acetylthio)acetamido]benzoate in the procedure ofCompound 1, there is provided, respectively

4-(2-MERCAPTOPROPIONAMIDO)BENZOIC ACID and

4-(3-MERCAPTOPROPIONAMIDO)BENZOIC ACID.

Compound 2

To a mixture of methyl 3-[2-(acetylthio)acetamido]benzoate (15 g., 0.056mole) in 100 ml. of ethanol is added 72 ml. (0.18 mole) of 10% sodiumhydroxide solution over a period of 10 minutes. The reaction mixture isstirred for a period of 16 hr. and acidified with 6 N hydrochloric acidto provide a solid which is collected, washed with water and dried,yielding 11.5 g., (97% yield) of the mercaptobenzoic acid product as awhite solid. Crystallization of the solid from anhydrous ethanol affordsanalytically pure 3-(2-MERCAPTOACETAMIDO)BENZOIC ACID, m.p.217.0°-219.0° C.

Analysis. Calcd. for C₉ H₉ NO₃ S: C, 51.17; H, 4.29; N, 6.63. Found: C,51.15; H, 4.41; N, 6.42.

Compound 3

To a slurry of N-[2-(acetylthio)acetyl]sulfanilic acid potassium salt(6.5 g., 0.02 mole) in 50 ml. of methanol is added dropwise 4 ml. (0.04mole) of 10 N potassium hydroxide while maintaining a temperature of25°-30° C. The reaction mixture is stirred for 3 hr. during which time asolution is obtained. Acetic acid (1.5 ml., 0.025 mole) is then slowlyadded to the reaction mixture to provide a white solid which iscollected, washed with methanol and dried affording 5.4 g. (95% yield)of analytically pure N-(2-MERCAPTOACETYL)SULFANILIC ACID POTASSIUM SALT,m.p. 335.0°-336.0° C. (dec.)(corr.).

Analysis. Calcd. for C₈ H₈ NO₄ S₂.K: C, 33.67; H, 2.83; N, 4.91. Found:C, 33.45; H, 2.88; N, 4.74.

By substituting the sodium salt of N-[2-(acetylthio)acetyl]sulfanilicacid and sodium hydroxide in place of the potassium salt and potassiumhydroxide, respectively, according to the above procedure, there isprovided N-(2-MERCAPTOACETYL)SULFANILIC ACID SODIUM SALT.

By substituting an equimolar amount of3-[2-(acetylthio)acetamido]benzensulfonic acid potassium salt or4-[2-(acetylthio)propionamido]benzenesulfonic acid potassium salt or4-[3-(acetylthio)propionamido]benzenesulfonic acid potassium salt,respectively, for N-[2-(acetylthio)acetyl]sulfanilic acid potassium saltin the procedure of Compound 3, there is provided

3-(2-MERCAPTOACETAMIDO)BENZENESULFONIC ACID POTASSIUM SALT,

4-(2-mercaptopropionamido)benzenesulfonic acid potassium salt, and

4-(3-MERCAPTOPROPIONAMIDO)BENZENESULFONIC ACID POTASSIUM SALT.

Compound 4

To a mixture of 4-[2-(acetylthio)acetamido]-N-(2-hydroxyethyl)benzamide(19.5 g., 0.066 mole) in 200 ml. of methanol is added 13.4 ml. (0.134mole) of a 40% solution of sodium hydroxide over a period of 5 minutes.After stirring for 1 hr., the mixture is acidified with 23 ml. (0.138mole) of 6 N hydrochloric acid, filtered and the filtrate diluted with125 ml. of water. After cooling the reaction mixture at acetone-dry icebath temperature, the precipitate which forms is collected, washed with50% ethanol and dried affording 14 g. (83% yield) of product.Crystallization of this material from ethanol provides analytically pureN-(2-HYDROXYETHYL)-4-(2-MERCAPTOACETAMIDO)BENZAMIDE, m.p. 184.0°-186.0°C. (corr.).

Analysis. Calcd. for C₁₁ H₁₄ N₂ O₃ S: C, 51.95; H, 5.55; N, 11.01.Found: C, 51.74; H, 5.47; N, 10.81.

Compound 5

To a suspension of 4-(2-chloroacetamido)benzoic acid (6.4 g., 0.03 mole)in 75 ml. of water is added slowly 30 ml. (0.33 mole) of 1 N potassiumhydroxide while maintaining a temperature of 10° C. When the addition iscomplete, potassium thiolacetate (3.5 g., 0.06 mole) is added at 25° C.,and the reaction mixture then stirred for a period of 16 hr. andfiltered. Acidification of the filtrate with hydrochloric acid providesan 87% yield of product. Crystallization of this material from ethanolaffords analytically pure 4-[2-(ACETYLTHIO)ACETAMIDO]BENZOIC ACID, m.p.233°-234° C.

Analysis. Calcd. for C₁₁ H₁₁ NO₄ S: C, 52.16; H, 4.38; N, 5.53; S,12.66. Found: C, 52.20; H, 4.34; N, 5.44; S, 12.40.

By substituting equimolar amounts of 4-(2-chloropropionamido)benzoicacid or 4-(3-chloropropionamido)benzoic acid for4-(2-chloroacetamido)benzoic acid in the procedure of Compound 5 thereis provided, respectively

4-[2-(ACETYLTHIO)PROPIONAMIDO]BENZOIC ACID and

4-[3-(ACETYLTHIO)PROPIONAMIDO]BENZOIC ACID.

By substituting equimolar amounts of the potassium salt of

thiolpropionic acid,

thioloctanoic acid,

thiolhexadecanoic acid,

thiolisobutyric acid,

respectively, for potassium thiolacetate in the procedure of Compound 5there is provided, respectively

4-[2-(PROPIONYLTHIO)ACETAMIDO]BENZOIC ACID,

4-[2-(octanoylthio)acetamido]benzoic acid,

4-[2-(hexadecanoylthio)acetamido]benzoic acid, and

4-[2-(ISOBUTYROYLTHIO)ACETAMIDO]BENZOIC ACID.

Compound 6

A mixture of methyl 4-(2-chloroacetamido)benzoate (4.2 g., 0.0184 mole)and potassium thiolacetate (2.2 g., 0.019 mole) in 75 ml. of acetone isrefluxed for 16 hr., filtered and the filtrate concentrated underreduced pressure. The residual solid thus obtained is dissolved in ethylacetate, treated with decolorizing charcoal and then diluted withn-hexane to afford an 81% yield of crude acetylthioester.Crystallization of the crude product from ethyl acetate-n-hexane affordsanalytically pure METHYL 4-[2-(ACETYLTHIO)ACETAMIDO]BENZOATE, m.p.137.0°-139.0° C. (corr.).

Analysis. Calcd. for C₁₂ H₁₃ NO₄ S: C, 53.92; H, 4.90; N, 5.24. Found:C, 53.98; H, 4.92; N, 5.03.

Compound 7

A mixture of methyl 3-(2-chloroacetamido)benzoate (16 g., 0.07 mole) andpotassium thiolacetate (7.1 g., 0.065 mole) in 150 ml. of acetone isrefluxed for 4.5 hr. After cooling, the reaction mixture is filtered andthe filtrate concentrated under reduced pressure. The residual solidthus obtained is slurried with n-hexane to afford an 86% yield of crudeproduct. Crystallization of the crude product from ethylacetate-n-hexane affords analytically pure METHYL3-[2-(ACETYLTHIO)ACETAMIDO]BENZOATE, m.p. 117.5°-119.5° C.

Analysis. Calcd. for C₁₂ H₁₃ NO₄ S: C, 53.92; H, 4.90; N, 5.24. Found:C, 53.98; H, 5.02; N, 4.89.

Compound 8

A mixture of 4-(2-chloroacetamido)-N-(2-hydroxyethyl)benzamide (39.3 g.,0.153 mole) and potassium thiolacetate (18.3 g., 0.16 mole) in 650 ml.of acetone is heated at reflux temperature for a period of 2 hr. Afterstanding overnight, the reaction mixture is filtered, the filtercakewashed with acetone, slurried with water, filtered and the filtercakewashed with water and dried to afford 34.7 g. of crude product.Crystallization of this material from ethyl acetate-methanol affordsanalytically pure4-[2-(ACETYLTHIO)ACETAMIDO]N-(2-HYDROXYETHYL)BENZAMIDE, m.p.190.0°-192.0° C. (corr.) in 57% yield.

Analysis. Calcd. for C₁₃ H₁₆ N₂ O₄ S: C, 52.69; H, 5.44; N, 9.45. Found:C, 52.64; H, 5.40; N, 9.18.

Compound 9

A mixture of N-(2-chloroacetyl)sulfanilic acid potassium salt (21 g.,0.073 mole) and potassium thiolacetate (8.8 g., 0.077 mole) in 100 ml.of dimethylformamide is stirred for a period of 3 hr. while maintaininga temperature of 50°-55° C. After standing for a period of 16 hr., thereaction mixture is filtered and the filter cake washed with diluteethanol. The crude acetylthio compound thus obtained is firstcrystallized from water, and then from water-ethanol using activatedcharcoal to provide analytically pure N-[2-(ACETYLTHIO)ACETYL]SULFANILICACID POTASSIUM SALT as a white solid, m.p. > 320.0° C.

Analysis. Calcd. for C₁₀ H₁₀ NO₅ S₂.K: C, 36.68; H, 3.08; N, 4.28.Found: C, 37.00; H, 3.23; N, 4.16.

EXAMPLE 3 Inhalation Compositions

A. powder For Administration via Inhaler Device

4-(2-mercaptoacetamido)benzoic acid, micronized: 2.5 g.

Lactose powder: 2.5 g.

The powders are blended asceptically and filled into hard gelatincapsules each containing 50 mg. of the mixture. This is suitable fordispersion into the inspired breath by means of a breath-operatedinhaler device containing means for rupture of the capsule wall prior todosing.

B. pressurized Aerosol Dispersion For Delivery of a Powder

4-(2-mercaptoacetamido)benzoic acid, micronized: 6.25 g.

Oleyl Alcohol: 0.1 g.

Dichlorodifluoromethane: 25.0 g.

Dichlorotetrafluoroethane: 68.65 g.

The micronized drug is dispersed in a solution of the other ingredientswhich has been cooled to -20° C. and filled into a chilled aerosolcontainer having a metered valve arranged to deliver 80 mg. of thecomposition at a single dose. This dose contains 5 mg. of activeingredient.

C. lyophilized Powder for Reconstitution

A solution of 1 g. disodium edeate, 10 g. of4-(2-mercaptoacetamido)benzoic acid and 90 g. of mannitol in 4 l. ofwater that is adjusted to pH 5.5 with sodium hydroxide solution issub-divided equally into 1000 ampoules. The ampoules are frozen and thefrozen mixture lyophilized to dryness. The ampoules are then sealed orcapped. For use, each ampoule is reconstituted with 4 ml. of a solutionhaving the following composition.

Sodium chloride: 0.4% w/w

Sodium hydroxide or hydrochloric acid, q.s: pH 6.5

Purified water, q.s: 4.0 ml.

D. sterile Lyophilized Powder

A solution of 20 g. of 4-(2-mercaptoacetamido)benzoic acid and 20 g. ofpolyvinylpyrrolidone C-30 (average molecular weight about 40,000) isdissolved in 8 1. of water, sub-divided into 1000 sterile glass vialsusing a sterilizing filter and aseptically lyophilized to dryness. Thevials are aseptically bacterial sealed. A suitable solvent forreconstitution of the sterile powder is sterile aqueous 0.9% sodiumchloride in purified water adjusted to pH 6.5. A 20 mg. dose of thecomposition is reconstituted with 4 ml. of this vehicle before use.

E. sterile Solution

4-(2-mercaptoacetamido)benzoic acid: 10.0 g.

Disodium edetate: 0.5 g.

Sodium hydroxide to pH 6.5

Purified, distilled and deoxygenated water, q.s: 1000 ml.

The above solution is prepared under a nitrogen atmosphere andaseptically filled into sterile ampoules using a sterilizing filter. Thefilled ampoules are immediately flushed with sterile nitrogen and flamesealed.

Composition C and D may be administered by a conventional nebulizingapparatus or by an intermittent pressure breathing apparatus. An equalweight of a pharmaceutically acceptable salt of4-(2-mercaptoacetamido)benzoic acid may be substituted for the free acidin Compositions A through E, if desired.

What is claimed is:
 1. A process for liquefaction of mucus whichcomprises contacting said mucus with a mucolytically effective amount ofa member selected from the group consisting of compounds having FormulaI ##STR6## wherein A is meta or para CONHCH₂ CH₂ OH;Alk is a straight orbranched divalent alkylene radical of from 1 to 3 carbon atomsinclusive; and R is hydrogen.
 2. The process as claimed in claim 1wherein said contacting step is carried out within the respiratory tractof a mammal.
 3. The process as claimed in claim 1 wherein saidcontacting step is carried out in vitro.
 4. The process as claimed inclaim 1 wherein said compound isN-(2-hydroxyethyl)-4-(2-mercaptoacetamido)benzamide. 5.N-(2-Hydroxyethyl)-4-(2-mercaptoacetamido)benzamide.